The present invention is concerned with 5,6,6a,7-Tetrahydro-4H-dibenz(de,g)isoquinoline derivatives, with a process for their preparation, with pharmaceutical compositions containing them and with their use for combating diseases of the central nervous system.
Federal Republic of Germany Patent Specification No. 2,757,281 describes an oxidative ring closure reaction of 1-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline derivatives by means of vanadium oxytrichloride which, without the introduction of a protective group on the nitrogen atom, proceeds smoothly and completely to give the 1-hydroxyaporphin system. An analogous reaction of 4-benzyltetrahydroisoquinoline with vanadium oxytrifluoride to give dibenz(de,g)isoquinoline is described in Tetrahedron, 35, 2555-2562/1979. This reference describes two compounds having similar structures to the compounds of the invention (reference compounds 9a and 9b), but these bases could only be isolated in 67% and 38% yields respectively from multicomponent mixtures. No utility for these compounds has previously been described.
Surprisingly, we have now found that the ring closure reaction of 4-benzyltetrahydroisoquinolines can give considerably purer products and correspondingly higher yields can be achieved when vanadium oxytrichloride is used instead of vanadium oxytrifluoride. This course of the reaction was not to have been expected since despite the modifications in the reaction described in the Tetrahedron article (loc. cit.), the reaction gave rise to black, tarry multicomponent mixtures when the synthesis of other bases was attempted. The authors were unable to find a generally useful, efficient means to prepare the dibenz(de,g)isoquinolines.
In addition to solving the synthetic problem, we have found that the dibenz(de,g)isoquinolines prepared according to the process of the present invention display valuable pharmacological properties and possess, in particular, a good neuroleptic action.
Therefore, they are especially useful for treating diseases of the central nervous system, for example, schizophrenia and Parkinson's disease, and endogenic depressions.
This discovery is also surprising since related 4-benzylisoquinolines (cf. Federal Republic of Germany Patent Specification No. 2,034,588, column 8, lines 54-57), which are typical spasmolytics, display a completely different activity profile and, even in the case of considerable dosages, do not exert any action on the central nervous system (see column 11, lines 9-15).